Abstract
Enteric bacterial pathogens such as enterohemorrhagic E. coli (EHEC) and Salmonella Typhimurium target the intestinal epithelial cells (IEC) lining the mammalian gastrointestinal tract. Despite expressing innate Toll-like receptors (TLRs), IEC are innately hypo-responsive to most bacterial products. This is thought to prevent maladaptive inflammatory responses against commensal bacteria, but it also limits antimicrobial responses by IEC to invading bacterial pathogens, potentially increasing host susceptibility to infection. One reason for the innate hypo-responsiveness of IEC is their expression of Single Ig IL-1 Related Receptor (SIGIRR), a negative regulator of interleukin (IL)-1 and TLR signaling. To address whether SIGIRR expression and the innate hypo-responsiveness of IEC impacts on enteric host defense, Sigirr deficient (−/−) mice were infected with the EHEC related pathogen Citrobacter rodentium. Sigirr −/− mice responded with accelerated IEC proliferation and strong pro-inflammatory and antimicrobial responses but surprisingly, Sigirr −/− mice proved dramatically more susceptible to infection than wildtype mice. Through haematopoietic transplantation studies, it was determined that SIGIRR expression by non-haematopoietic cells (putative IEC) regulated these responses. Moreover, the exaggerated responses were found to be primarily dependent on IL-1R signaling. Whilst exploring the basis for their susceptibility, Sigirr −/− mice were found to be unusually susceptible to intestinal Salmonella Typhimurium colonization, developing enterocolitis without the typical requirement for antibiotic based removal of competing commensal microbes. Strikingly, the exaggerated antimicrobial responses seen in Sigirr −/− mice were found to cause a rapid and dramatic loss of commensal microbes from the infected intestine. This depletion appears to reduce the ability of the microbiota to compete for space and nutrients (colonization resistance) with the invading pathogens, leaving the intestine highly susceptible to pathogen colonization. Thus, SIGIRR expression by IEC reflects a strategy that sacrifices maximal innate responsiveness by IEC in order to promote commensal microbe based colonization resistance against bacterial pathogens.
Highlights
Citrobacter rodentium is a mouse-specific attaching/effacing (A/E) bacterial pathogen related to the clinically important enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli (EHEC)
Sigirr 2/2 mice develop exaggerated colitis during C. rodentium infection. While it is unclear why intestinal epithelial cell (IEC) play such a limited role in driving MyD88 dependent responses to C. rodentium infection and other forms of colitis [23,24,25], we recently showed that Single Ig IL-1 Related Receptor (SIGIRR), a negative regulator of Toll-like receptors (TLRs) and IL-1R signaling, is expressed by IEC and limits their responses to IL-1b and to most bacterial PAMPs [20]
MyD88 dependent signaling plays a critical protective role during C. rodentium infection, promoting inflammatory and antimicrobial responses that control C. rodentium burdens, as well as homeostatic responses that protect IEC barrier function and limit/repair IEC injury [5,6]. While many of these responses involve changes in IEC function, we clearly show that MyD88 signaling within IEC plays little role in driving these responses
Summary
Citrobacter rodentium is a mouse-specific attaching/effacing (A/E) bacterial pathogen related to the clinically important enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli (EHEC). C. rodentium has been widely used to define the in vivo virulence strategies employed by A/E pathogens [1,2]. It has proven a popular model to assess host immune responses against mucosal bacterial pathogens as well as explore how these pathogens compete with intestinal commensal microbes for colonization niches and nutrients [3,4]. We and others have shown that infected Myd deficient (2/2) mice suffer severe intestinal epithelial cell (IEC) damage leading to widespread ulcers and necrosis of their colonic tissues. MyD88 signaling appears to limit tissue damage during infection by this pathogen, potentially by promoting increased IEC proliferation [5,6]
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